The infection of macaques by simian immunodeficiency virus (SIV) results in many of the events characteristic of human immunodeficiency virus (HIV) infection and progression to acquired immunodeficiency syndrome (AIDS) in humans. This nonhuman primate model has therefore been extensively studied in an attempt to develop vaccines against AIDS. We have shown that protective immunity in macaques can be elicited by immunization with a recombinant vaccinia virus expressing SIV/Mne gp160 followed by boosting with gp160. The immunized animals were protected against an intravenous or an intrarectal challenge with the homologous virus grown in macaque peripheral blood mononuclear cells. Additional vaccine studies are underway that will test whether vaccinia virus expressing gp120 or vaccinia virus expressing gag and/or pol are as effective in protecting macaques from challenges with homologous and heterologous virus stocks. It has been reported that protection from infection elicited by whole virus vaccines might have been due to cellular antigens in the vaccine preparations and in the virus challenge stocks. We have identified the cellular proteins present in SIV and HIV virus preparations and shown that antisera to these viral-associated- major histocompatibility complex-coded human proteins neutralize in vitro infection of HIV-1 and SIV. To determine if an immune response to these antigens protects from an in vivo virus challenge, macaques were immunized with uninfected human cells, gradient-purified culture fluid from uninfected human cells, beta-2-microglobulin (beta2M), immunoaffinity-purified human HLA class I and class II proteins (HLA-DR) or adjuvant. The macaques immunized with beta2M, HLA class I, and uninfected human cells were not protected from a challenge with SIV grown in human cells. In contrast, the macaques immunized with HLA-DR developed high antibody titers to HLA-DR and were protected from virus challenge. These results clearly demonstrate that an immune response to purified cellular antigens is protective and identify HLA-DR as a cellular component on the surface of SIV involved in this protection.